tbuckley/cabot-search huggingface dataset:
Mortality Among Parkinson’s Disease Patients Treated With Pimavanserin or Atypical Antipsychotics: An Observational Study in Medicare Beneficiaries
Authors: Andrew D. Mosholder, Yong Ma, Sandia Akhtar, Gerald D. Podskalny, Yuhui Feng, Hai Lyu, Jiemin Liao, Yuqin Wei, Michael Wernecke, Kira Leishear, Lorene M. Nelson, Thomas E. MaCurdy, Jeffrey A. Kelman, David J. Graham
Journal: American Journal of Psychiatry (2022)

Pimavanserin, a serotonin 5-HT2 antagonist, is indicated for treatment of hallucinations and delusions associated with Parkinson's disease psychosis. In premarketing trials in patients with Parkinson's disease psychosis, 11% of patients died during open-label pimavanserin treatment. Antipsychotics, which are used off-label in Parkinson's disease psychosis, increase mortality in dementia patients. The authors compared mortality with pimavanserin and atypical antipsychotics in a large database.This was a retrospective new-user cohort study of Medicare beneficiaries with Parkinson's disease initiating pimavanserin (N=3,227) or atypical antipsychotics (N=18,442) from April 2016 to March 2019. All-cause mortality hazard ratios and 95% confidence intervals were estimated for pimavanserin compared with atypical antipsychotics, using segmented proportional hazards regression over 1-180 and 181+ days of treatment. Potential confounding was addressed through inverse probability of treatment weighting (IPTW).Pimavanserin users had a mean age of approximately 78 years, and 45% were female. Before IPTW, some comorbidities were more prevalent in atypical antipsychotic users; after IPTW, comorbidities were well balanced between groups. In the first 180 days of treatment, mortality was approximately 35% lower with pimavanserin than with atypical antipsychotics (hazard ratio=0.65, 95% CI=0.53, 0.79), with approximately one excess death per 30 atypical antipsychotic-treated patients; however, during treatment beyond 180 days, there was no additional mortality advantage with pimavanserin (hazard ratio=1.05, 95% CI=0.82, 1.33). Pimavanserin showed no mortality advantage in nursing home patients.Pimavanserin use was associated with lower mortality than atypical antipsychotic use during the first 180 days of treatment, but only in community-dwelling patients, not nursing home residents.
Abstract 3071: A reconstruction of evolutionary trajectories in primary tissue and PDTOs in a patient with metastatic osteosarcoma
Authors: Ardy Davarifar, Jane Yanagawa, Ahmad Al Shihabi, Huyen T. Nguyen, Lydia Y. Liu, Adriana Salcedo, Alfredo Gonzalez, Takafumi N. Yamaguchi, Nicholas Bernthal, Scott D. Nelson, Noah Federman, Paul C. Boutros, Alice Soragni
Journal: Cancer Research (2022)

Abstract Metastatic osteosarcoma is a rare and highly lethal cancer that affects children and young adults. The rarity of osteosarcoma and its highly heterogeneous genetic composition have resulted in a lack of curative treatments for recurrent and metastatic disease. In this study, we present the functional and molecular characterization of a case of a pediatric patient with left distal femur osteosarcoma and pulmonary metastases at presentation. Through longitudinal sampling over the course of the patient’s illness, we have procured tissue from the initial treatment-naïve diagnostic biopsy, primary tumor resection and multiple subsequent lung metastasectomies, and have developed patient-derived tumor organoids (PDTOs) from the viable samples. PDTOs are useful pre-clinical models that are representative of the source tissue and allow further interrogations of the biology of tumors. These models can also help with the identification of effective personalized therapies (Al Shihabi et al, 2021). We applied our mini-ring organoid screening technology (Phan et al, 2019; Nguyen et al, 2020) to perform high-throughput drug screening with different pharmacologic agents. We also performed deep whole-genome sequencing on all collected samples and corresponding organoids to reconstruct their evolutionary history, identify driver mutations and quantify heterogeneity in mutational processes across time and space. Our preliminary data show that the subclonal content of the tumor and derivative organoids as well as the PDTO drug responses vary with the patient’s treatment history. We identify the genomic makeup of the subclones and posit changes that may be responsible for chemoresistance. Furthermore, our data shows correlations between the subclonal genomic composition of the PDTOs and source tissue, thereby reinforcing that PDTOs are capable of accurately recapitulating the subclonal heterogeneity of the parental tumor. Citation Format: Ardy Davarifar, Jane Yanagawa, Ahmad Al Shihabi, Huyen T. Nguyen, Lydia Y. Liu, Adriana Salcedo, Alfredo Gonzalez, Takafumi N. Yamaguchi, Nicholas Bernthal, Scott D. Nelson, Noah Federman, Paul C. Boutros, Alice Soragni. A reconstruction of evolutionary trajectories in primary tissue and PDTOs in a patient with metastatic osteosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3071.
Abstract CT529: A Phase 1b Study of CG0070 combined with nivolumab in cisplatin ineligible patients with muscle invasive bladder cancer
Authors: Roger Li, Wade Sexton, Phillipe Spiess, Scott Gilbert, Julio Pow-Sang, Jingsong Zhang, Gustavo Borjas, Paola Grandi, James Burke, Rohit Jain, Jose Conejo-Garcia
Journal: Cancer Research (2022)

Abstract Background: Up to 50% of patients with muscle invasive bladder cancer (MIBC) are unable to receive neoadjuvant chemotherapy, creating an unmet clinical need for alternative systemic treatment. Results from recent neoadjuvant immune checkpoint blockade (ICB) studies signal pCR rates between 31-42%. However, there was a clear dichotomy in response between patients with high vs. low pre-treatment lymphocytic infiltration. In tumors exhibiting immune excluded or immune desert phenotypes, therapeutic strategies to attract CD8+ T cells infiltration prior to ICB may be beneficial. CG0070 is an oncolytic adenovirus designed to preferentially replicate through a transcriptionally regulated promoter that is up-regulated in RB-pathway-defective cells (&amp;gt;70% of MIBC). In addition, CG0070 expresses GM-CSF to attract antigen presenting cells to the tumor microenvironment. We hypothesize that combination therapy using intravesical CG0070 and systemic Nivolumab is 1) safe and 2) can enhance local and systemic treatment response in the neoadjuvant setting against MIBC. Methods: This is a phase Ib trial evaluating 2 doses of nivolumab (4 weeks apart) with 6 weekly intravesical CG0070 followed by cystectomy. Dose-limiting toxicities (DLTs) will be assessed in 6 DLT-evaluable patients in a safety lead-in phase. The combination would be declared tolerable if the incidence of DLTs is &amp;lt;33%, and the study expanded to 30 patients. Key eligibility: cT2-T4aN0-1M0 stage, no autoimmume disease within 2 years, and no concurrent invasive upper tract carcinoma or other active cancer. The primary objective is to evaluate the safety of combination therapy according to CTCAE v5.0. The secondary objective is to assess the changes in the lymphocytic infiltration following combination therapy and to assess the antitumor efficacy of combination therapy. Exploratory endpoints include assessing the predictive value of E2F expression, tumor mutational burden, immune infiltration, and various peripheral blood for treatment response. Study Progress: Study is actively accruing. Clinical trial information: NCT04610671. An update on the study will be provided at the time of presentation. Citation Format: Roger Li, Wade Sexton, Phillipe Spiess, Scott Gilbert, Julio Pow-Sang, Jingsong Zhang, Gustavo Borjas, Paola Grandi, James Burke, Rohit Jain, Jose Conejo-Garcia. A Phase 1b Study of CG0070 combined with nivolumab in cisplatin ineligible patients with muscle invasive bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT529.
Abstract 603: Discovery of CD200R1 as a novel immuno-oncology target using pleiotropic signals from 23andMe’s genetic and health survey database
Authors: Xin Fang, Wei-Jen Chung, Jill Fenaux, Alice Chen, Nizar Batada, Maike Schmidt, Sophia R. Majeed, Sushil Kumar, Steven Pitts
Journal: Cancer Research (2022)

Abstract Using large genetic and phenotypic datasets, 23andMe has developed a novel immuno-oncology target-identification platform. 23andMe has assembled a genetic database of nearly 12 million individuals, with 80 percent consented to research, coupled with health survey data comprising billions of responses. We identified hundreds of shared GWAS signals across phenotypes that appear to be driven by pleiotropic causal variants whose direction of effect (risk versus protection) systematically differs across cancer and autoimmune diseases including a signal linked to a clinically validated immune checkpoint receptor. This observation suggests that genes linked to such signals may be utilized by tumor cells to evade the immune system. We hypothesize that such signals indicate nodes of critical importance for anti-tumor immune response. By utilizing expression quantitative trait loci (eQTLs) and coding single nucleotide polymorphisms (SNPs) to link these signals to causal effects on genes, we identified CD200R1, an inhibitory receptor expressed on T cells and myeloid cells, as an immune checkpoint target. Immune-oncology associations were observed in multiple components of the CD200R1 pathway, including the receptor, its cognate ligand, CD200, and its downstream adaptor protein, DOK2. Expression of CD200R1 was validated in tumor-infiltrating lymphocytes using bulk and single-cell RNA-seq from various tumor types. This genetics-driven target discovery platform facilitated the development of a fully humanized monoclonal antibody that binds CD200R1 on immune cells with high affinity and enhances killing of tumor cells expressing CD200. [X. F. and W-J. C. contributed equally to this work.] Citation Format: Xin Fang, Wei-Jen Chung, Jill Fenaux, Alice Chen, Nizar Batada, Maike Schmidt, Sophia R. Majeed, Sushil Kumar, Steven Pitts. Discovery of CD200R1 as a novel immuno-oncology target using pleiotropic signals from 23andMe’s genetic and health survey database [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 603.
Abstract 1146: A novel anti-Galectin-3 antibody therapeutic for the treatment of glioblastoma
Authors: ANNE MARIE BARRETTE, Krutika Deshpande, Marvin Cadiente, Anji Bei, Xi Wang, Teodelinda Mirabella, Dongxu Sun
Journal: Cancer Research (2022)

Abstract Characterized by rapid growth and diffusely infiltrative spread, glioblastoma (GBM) is the most common and most malignant primary brain cancer with a very poor prognosis and a standard of care that hasn’t been improved in over 15 years. The need for new therapies that can directly or indirectly target heterogeneous tumor cell populations to inhibit cell migration in addition to proliferation is highlighted by the recent efforts to develop targeted therapies to treat the vast majority of GBM patients whose tumors impede gross-total resection and develop resistance to chemoradiation. Galectin-3, a carbohydrate-binding protein overexpressed in astrocytes, microglia/macrophages, and the stroma of GBM tumors is a potent modulator of cell proliferation, migration, angiogenesis, T-cell inhibition, and M2 macrophage polarization. We and others have confirmed the association of Galectin-3 expression to lower survival in glioma patients. Additionally, tumor Galectin-3 levels have been shown to increase following exposure to temozolomide or radiation alone or in combination, thus more greatly increasing the need for targeting Galectin-3 in GBM patients following initial treatment. Here, we characterize the therapeutic effects of the anti-Galectin-3 antibody (Gal3 Ab) we have developed for the ability to inhibit GBM tumorigenic and metastatic potential in several in vitro assays and in vivo in heterotopic and orthotopic mouse models. Human GBM cells treated with Gal3 Ab show a significant decrease in cell viability, migration, and invasion in vitro. In vivo, the Gal3 Ab decreases tumor burden and provides a survival benefit in combination with temozolomide compared to the current standard-of-care treatment alone. Our studies indicate the potential for our novel anti-Galectin-3 to be added to the very limited arsenal of potential treatments for GBM. Citation Format: ANNE MARIE BARRETTE, Krutika Deshpande, Marvin Cadiente, Anji Bei, Xi Wang, Teodelinda Mirabella, Dongxu Sun. A novel anti-Galectin-3 antibody therapeutic for the treatment of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1146.
Abstract 5679: Application of a hypoxia metric to investigate tumor mutational burden and cancer cell immunogenicity <i>in vitro</i>
Authors: Raefa Abou Khouzam, Nagwa Ahmed Zeinelabdin, Mohak Sharda, Husam Nawafleh, Ayda shah Mahmood, Munazza Samar Khan, Goutham Hassan Venkatesh, Salem Chouaib, Shyama Prasad Rao
Journal: Cancer Research (2022)

Abstract Hypoxia afflicts the microenvironment of solid tumors fueling tumor malignancy. Using an 8-gene in vitro hypoxia signature, we have recently shown that pancreatic cancer patients with highly hypoxic tumors experience worse survival and exhibit markers of an immunosuppressed microenvironment. Simultaneously, we obtained evidence of increased mutation count in more hypoxic tumors, which accommodates previous reports associating hypoxia with the regulation of tumor mutational burden (TMB) and genomic instability. These two features could enhance tumor immunogenicity by increasing neoantigen expression, enabling immune recognition and tumor eradication. In this work our aim is to further elucidate the underlying role of hypoxia in generating TMB and genomic instability, and how it contributes to cancer cells immunogenicity. To this end, we applied our recently identified 8-gene hypoxia signature to score the hypoxic response of different cancer cells, considering their median expression levels of the signature genes upon exposure to hypoxia (1% oxygen). The hypoxia score was then applied as a metric to distinguish between the highest and lowest scoring cells, enabling a novel approach for evaluating the intrinsic impact of hypoxia on immunogenicity. After twenty passages under hypoxic conditions (1% oxygen), scored cancer cells were subjected to whole exome sequencing (WES) using the Ion Chef System. Following data processing using appropriate bioinformatic tools, variants were called in the hypoxia-treated cells using their normoxic (21% oxygen) counterparts as controls. We first demonstrated that hypoxia induced an increase in TMB in all cell lines. More interestingly, higher scoring cells were found to display, on average, higher TMB than lower scoring cells, suggesting that cells that have a lower hypoxia score tend to be less mutable. Copy number alterations, mutational signature and neoantigen load predictions generated from the WES data will be discussed. The microarray analysis of transcriptomic data from these hypoxia-treated cells, as well as the relationship between the high TMB, high neoantigen load and increased activation of immune response pathways will also be illustrated. Citation Format: Raefa Abou Khouzam, Nagwa Ahmed Zeinelabdin, Mohak Sharda, Husam Nawafleh, Ayda shah Mahmood, Munazza Samar Khan, Goutham Hassan Venkatesh, Salem Chouaib, Shyama Prasad Rao. Application of a hypoxia metric to investigate tumor mutational burden and cancer cell immunogenicity in vitro [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5679.
Abstract 6027: Layered 3D co-cultured tumor model including vascularized stromal tissue may reflect drug sensitivities in vivo tumor
Authors: Yuki Takahashi, Shiro Kitano, Eiji Shinozaki, Satoshi Nagayama, Ryohei Katayama, Naoya Fujita
Journal: Cancer Research (2022)

Abstract Background: Multiple 3D culture models have been reported as a superior tumor model than 2D culture. The importance of interaction between cancer and stromal cells has been widely recognized in tumor progression and resistance to treatment. Therefore, ex vivo model recapturing the tumor microenvironment is needed to evaluate the drug efficacy under the condition imitating the patient tumor tissue. Purpose: We developed a unique 3D co-cultured tumor model with stromal tissues containing a microvascular network. Here, we investigated drug sensitivity in conventional 2D culture, our 3D co-cultured model and in vivo tumor. Methods: Drug sensitivity and gene expression on our model were evaluated using patient-derived cancer cells (PDC) established from colorectal cancer (CRC) patients in JFCR. The characteristics were compared with those of conventional 2D cultured cells or patient-derived xenograft (PDX). Results: In our 3D model, the drug sensitivities tended to be decreased in comparison with those of 2D. However, some drugs presented potent efficacy in our 3D model rather than 2D, and such drugs showed significant tumor growth suppression or tumor regression in vivo. Transcriptome profiles of our 3D model showed relatively higher similarity to those of in vivo tumors than those of 2D. Conclusion: Our study proposed the unique 3D co-cultured tumor model which may enable more accurate evaluation of drug sensitivities reflecting the in vivo circumstances. Citation Format: Yuki Takahashi, Shiro Kitano, Eiji Shinozaki, Satoshi Nagayama, Ryohei Katayama, Naoya Fujita. Layered 3D co-cultured tumor model including vascularized stromal tissue may reflect drug sensitivities in vivo tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6027.
Abstract 1030: IX2X2
Authors: Thamarai U. Ponnusamy, Thirumagal T. Thiyagarajan, Ramesh Narayanan
Journal: Cancer Research (2022)

Abstract Introduction: Prostate cancer (PCa) is the second leading cause of cancer-related mortality in men. More than 85% of PCa and advanced aggressive castration-resistant prostate cancer (CRPC) depend on the androgen receptor (AR) for growth. AR-targeted therapeutics are the mainstay treatment option for PCa. Majority of PCa and CRPC respond to AR-LBD-binding antagonists such as enzalutamide and become refractory after a brief period of response. One of the main resistance mechanisms is the expression of AR splice variants (AR-SVs). AR-SVs lack LBD and are constitutively active, causing aggressive phenotype. Description: Rationale-based drug design was employed to synthesize selective AR irreversible covalent antagonists (SARICA). SARICAs were evaluated in AR transactivation to determine the antagonistic activity. SARICAs were incubated with purified recombinant AR activation function-1 (AF-1) protein and mass spectrometry was performed to determine their covalent binding. SARICAs were evaluated in AR-SV transactivation assay and in a Schild’s plot to determine the nature of inhibition (reversible Vs irreversible). SARICAs were tested in PCa cell line gene expression and proliferation assays and in tumor xenograft experiments. Summary: SARICAs inhibited AR transactivation in submicromolar range. Mass spectrometry with purified AF-1 protein demonstrated covalent binding of SARICAs and identified C406 and C327 as SARICA-interacting nucleophiles. Both amino acids are important for AR-V7 function and stability, making them appropriate drug targets. SARICAs inhibited the activity of AR-V7 and irreversibly inhibited AR transactivation, indicating that these covalent binders are irreversible antagonists. SARICAs selectively inhibit the proliferation and growth of AR-positive prostate cancer cells and tumors, but not AR-negative cells and tumors. Conclusion: These first-in-class AR-selective covalent molecules thus serve as chemical probes to advance our understanding of the AR-AF-1 and they potentially offer an opportunity to treat refractory cancers. Disclosure: This work was supported by an NCI grant (CA229164 and CA229164S1), a DOD grant (W81XWH2110055), and by Muirhead endowment. The SARICAs are licensed to Oncternal therapeutics, San Diego, CA. RN is a consultant to Oncternal therapeutics. Citation Format: Thamarai U. Ponnusamy, Thirumagal T. Thiyagarajan, Ramesh Narayanan. IX2X2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1030.
Abstract 3451: Microglial phagocytosis suppressed the development of metastatic tumors in the imaging model of brain metastasis
Authors: Takahiro Tsuji, Hiroaki Wake, Mariko Shindo, Daisuke Kato, Hiroaki Ozasa, Toyohiro Hirai
Journal: Cancer Research (2022)

Abstract Brain metastasis of lung cancer is a crucial problem that causes poor clinical outcomes and alters patient quality of life. Previous evidence showed that lung cancer cells (LUCs) may escape from host immunity to form distant metastases. We previously used an original imaging model of brain metastasis (IBrM) to show a heterogeneous interaction between microglia, the tissue macrophages in the brain, and LUCs in the brain niche. The findings confirmed that microglia can phagocytose metastatic cancer cells. Here, we show that genetic deletion of the “don’t eat me” signals of cancer cells can promote phagocytic activity of microglia against LUCs. We injected an adenocarcinoma lung cancer cell line expressing mCherry (CMT167mC) via the internal carotid artery of the CX3CR1-EGFP mice, whose microglia had been specifically labeled with EGFP. The microglia and LUCs were visualized in vivo simultaneously by two-photon microscopy for 14 days. The tumor fate and microglial response against cancer cells were evaluated at single cell resolution in the IBrM. CD24, CD47, and/or PDL1 were deleted in CMT167mC cells using CRISPR/Cas9 to examine the effect of the “don’t eat me” signals. The dynamic behavior of LUCs and the microglial phagocytosis activity against LUCs were visualized in living mice. Microglial phagocytosis was significantly increased by single deletion of CD47 or CD24 compared with WT cells. Combined deletion of CD47 and CD24 also synergically increased microglial phagocytosis, resulting in reduced IBrM and prolonged mouse survival. By contrast, deletion of PD-L1 did not enhance microglial phagocytosis or prolong survival. The pharmacological or genetic conditional depletion of microglia canceled both the increased phagocytosis and the extended survival time, suggesting that the effect of “don't eat me” signals was microglia-dependent. These results indicate that suppression of both CD24 and CD47 in LUCs enhances microglial phagocytic activity and suppresses the metastatic formation of LUCs. Furthermore, the combined use of CRISPR/Cas9 in LUCs and in vivo imaging allows us to evaluate potential therapeutic targets associated with microglial phagocytosis. We are currently using single cell RNA-seq and cell-to-cell communication analysis of the brain tumor and surrounding niche to explore other signal pathways that regulate tumor phagocytosis by microglia and to identify potential therapeutic targets. Citation Format: Takahiro Tsuji, Hiroaki Wake, Mariko Shindo, Daisuke Kato, Hiroaki Ozasa, Toyohiro Hirai. Microglial phagocytosis suppressed the development of metastatic tumors in the imaging model of brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3451.